title: Combination of multifaceted strategies to maximize the therapeutic benefits of neural stem cell transplantation for spinal cord repair.
abstract: Neural stem cells (NSCs) possess therapeutic potentials to reverse complex pathological processes following spinal cord injury (SCI), but many obstacles remain that could not be fully overcome by NSC transplantation alone. Combining complementary strategies might be required to advance  NSC-based treatments to the clinical stage. The present study was undertaken to examine whether combination of NSCs, polymer scaffolds, neurotrophin-3 (NT3), and chondroitinase, which cleaves chondroitin sulfate proteoglycans at the interface between spinal cord and implanted scaffold, could  provide additive therapeutic benefits. In a rat hemisection model, poly(ɛ-caprolactone) (PCL) was used as a bridging scaffold and as a vehicle for NSC delivery. The PCL scaffolds seeded with F3 NSCs or NT3 overexpressing F3 cells (F3.NT3) were implanted into hemisected cavities. F3.NT3  showed better survival and migration, and more frequently differentiated into neurons and oligodendrocytes than F3 cells. Animals with PCL scaffold containing F3.NT3 cells showed the best locomotor recovery, and motor evoked potentials (MEPs) following transcranial magnetic stimulation were  recorded only in PCL-F3.NT3 group in contralateral, but not ipsilateral, hindlimbs. Implantation of PCL scaffold with F3.NT3 cells increased NT3 levels, promoted neuroplasticity, and enhanced remyelination of contralateral white matter. Combining chondroitinase treatment after PCL-F3.NT3 implantation  further enhanced cell migration and promoted axonal remodeling, and this was accompanied by augmented locomotor recovery and restoration of MEPs in ipsilateral hindlimbs. We demonstrate that combining multifaceted strategies can maximize the therapeutic benefits of NSC transplantation for  SCI. Our results may have important clinical implications for the design of future NSC-based strategies.
authors.affiliation: Brain Disease Research Center, Institute of Medical Sciences, Ajou University School of Medicine, Suwon, Republic of Korea.
authors.forename: Dong H
authors.initials: DH
authors.lastname: Hwang
authors.forename: Hyuk M
authors.initials: HM
authors.lastname: Kim
authors.forename: Young M
authors.initials: YM
authors.lastname: Kang
authors.forename: In S
authors.initials: IS
authors.lastname: Joo
authors.forename: Chong-Su
authors.initials: CS
authors.lastname: Cho
authors.forename: Byung-Woo
authors.initials: BW
authors.lastname: Yoon
authors.forename: Seung U
authors.initials: SU
authors.lastname: Kim
authors.forename: Byung G
authors.initials: BG
authors.lastname: Kim
mesh_terms: D000818:Animals; D001369:Axons / Q000187:drug effects / Q000378:metabolism; D001522:Behavior, Animal / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D011508:Chondroitin Sulfate Proteoglycans / Q000378:metabolism; D003131:Combined Modality Therapy; D019054:Evoked Potentials, Motor / Q000187:drug effects; D005260:Female; D006801:Humans; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D058953:Neural Stem Cells / Q000166:cytology / Q000637:transplantation* / Q000648:ultrastructure; D020933:Neurotrophin 3 / Q000494:pharmacology; D010641:Phenotype; D011091:Polyesters / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D020127:Recovery of Function / Q000187:drug effects; D013116:Spinal Cord / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology / Q000601:surgery; D058630:Spinal Cord Regeneration / Q000187:drug effects; D033581:Stem Cell Transplantation; D054457:Tissue Scaffolds / Q000737:chemistry
chemical_list: D011508:Chondroitin Sulfate Proteoglycans; D020933:Neurotrophin 3; D011091:Polyesters; C016240:polycaprolactone